The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition

Abstract

Aggressive B-cell malignancies, such as mantle cell lymphoma (MCL), are microenvironment-dependent tumors and a better understanding of the dialogs occurring in lymphoma protective ecosystems will provide new perspectives to increase treatment efficiency. To identify novel molecular regulations, we performed a transcriptomic analysis based on the comparison of circulating (n=77) versus MCL lymph nodes (n=107) together with RNA sequencing of malignant (n=8) versus normal B-cell (n=6) samples. This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of the interleukin-32 beta (IL32β), whose expression was confirmed in situ within MCL lymph nodes by multiplex immunohistochemistry. Using ex vivo models of primary MCL cells (n=23), we demonstrated that, through the secretion of IL32β, the tumor was able to polarize monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFNB inhibition to counteract microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. This data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophages polarization and tumor survival, which could be counteracted through selective NIK inhibition.

Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma

“…In contrast, whereas stromal cells protected MCL cells against spontaneous apoptosis, they were not able to promote robust proliferation in this model. Based on integrated transcriptomic and functional analysis, they showed that peripheral blood MCL cells cultured in the presence of CD40-L and cytokine stimuli displayed cellular (proliferation, survival) and molecular (NF-kB pathways, Bcl-2 family, secretome) profiles similar to the ones seen in lymph-node-resident MCL cells, emphasizing the relevance of the model and the role of CD40-L expressing T cells for tumor survival [28,33,36]. Further characterization of MCL TME in situ is now needed to characterize these T-cell populations.…”

“…More recently, Decombis et al demonstrated that MCL cells also present a tumorspecific secretion of interleukin-32 beta (IL32β) through CD40-L-mediated interaction with the TME, but also IL32 locus hypomethylation. This secretion is dependent on the alternative NF-κB pathway (NF-kB2) and is able to differentiate monocytes into specific CD163 macrophages, supporting MCL cell survival through a soluble dialog mostly driven by BAFF (a member of the tumor necrosis factor (TNF) family), making the IL32/BAFF axis a novel key target to be disrupted, potentially targeting the NIK/NF-kB2 pathway [36]. The role of the BAFF/BAFF-R axis in the pathogenesis of MCL has also been supported in other studies [42][43][44][45].…”

Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

“…The third group of cells which modulate the survival of lymphoma cells are the macrophages. MCL cells attract monocytes and promote them to differentiate into tumor-associated M2 macrophages (TAM) [ 37 , 38 ]. The precise role for TAMs in MCL is still unknown, although recent studies indicate that TAMs induce MCL growth via secretion of, e.g., IL-10 and BAFF [ 32 , 37 , 38 ].…”

“…MCL cells attract monocytes and promote them to differentiate into tumor-associated M2 macrophages (TAM) [ 37 , 38 ]. The precise role for TAMs in MCL is still unknown, although recent studies indicate that TAMs induce MCL growth via secretion of, e.g., IL-10 and BAFF [ 32 , 37 , 38 ]. Interestingly, T cells also play a role by CD40-mediated induction of IL-32β, which in turn instructs the TAMS to secrete BAFF [ 38 , 39 ].…”

“…The precise role for TAMs in MCL is still unknown, although recent studies indicate that TAMs induce MCL growth via secretion of, e.g., IL-10 and BAFF [ 32 , 37 , 38 ]. Interestingly, T cells also play a role by CD40-mediated induction of IL-32β, which in turn instructs the TAMS to secrete BAFF [ 38 , 39 ]. This is in concordance with the more established role of TAMs in CLL, where TAMs induce lymphoma survival via secretion of a proliferation-inducing ligand (APRIL), BAFF, CXCL12 and -13, and Wnt5a, and via stimulation of the BCR and CD38 [ 40 , 41 ].…”